(2R)-4-Oxo-4-[3-(Trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-
7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine: A Potent, Orally Active
Dipeptidyl Peptidase IV Inhibitor for the Treatment of Type 2 Diabetes
posted on 2005-01-13, 00:00authored byDooseop Kim, Liping Wang, Maria Beconi, George J. Eiermann, Michael H. Fisher, Huaibing He, Gerard J. Hickey, Jennifer E. Kowalchick, Barbara Leiting, Kathryn Lyons, Frank Marsilio, Margaret E. McCann, Reshma A. Patel, Aleksandr Petrov, Giovanna Scapin, Sangita B. Patel, Ranabir Sinha Roy, Joseph K. Wu, Matthew J. Wyvratt, Bei B. Zhang, Lan Zhu, Nancy A. Thornberry, Ann E. Weber
A novel series of β-amino amides incorporating fused heterocycles, i.e., triazolopiperazines,
were synthesized and evaluated as inhibitors of dipeptidyl peptidase IV (DPP-IV) for the
treatment of type 2 diabetes. (2R)-4-Oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine (1) is a potent, orally active DPP-IV inhibitor (IC50 = 18 nM) with excellent selectivity over other proline-selective peptidases,
oral bioavailability in preclinical species, and in vivo efficacy in animal models. MK-0431, the
phosphate salt of compound 1, was selected for development as a potential new treatment for
type 2 diabetes.